期刊
CELL REPORTS
卷 21, 期 10, 页码 2772-2784出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.021
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资金
- Medical Research Council UK [MR/N000528/1]
- Brain Tumour Research Centre of Excellence
- Pathological Society of Great Britain and Ireland [SGS 2013/04/03]
- Barts and the London Charity [527/2087]
- CAPES Foundation scholarship, Ministry of Education of Brazil
- Medical Research Council [MR/N026063/1, MR/N000528/1, G0902001] Funding Source: researchfish
- National Institute for Health Research [ACF-2007-19-003] Funding Source: researchfish
- MRC [MR/N000528/1, G0902001, MR/N026063/1] Funding Source: UKRI
We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1(High); CHD7(Low) expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7.
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